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In yeast and humans, an enzyme that plays a key role in repairing such damage are the PSO<\/jats:styled-content>2\/SNM<\/jats:styled-content>1 nucleases. Here, we report that T<\/jats:italic><\/jats:styled-content>rypanosoma brucei<\/jats:italic>, the causative agent of A<\/jats:styled-content>frican trypanosomiasis, possesses a bona fide<\/jats:italic> member of this family (called TbSNM<\/jats:styled-content>1) with expression of the parasite enzyme able to suppress the sensitivity yeast pso2\u0394<\/jats:italic><\/jats:styled-content> mutants display towards mechlorethamine, an ICL<\/jats:styled-content>\u2010inducing compound. By disrupting the T<\/jats:styled-content>bsnm1<\/jats:italic><\/jats:styled-content> gene, we demonstrate that TbSNM<\/jats:styled-content>1 activity is non\u2010essential to the medically relevant T<\/jats:italic><\/jats:styled-content>.\u2009brucei<\/jats:italic> life cycle stage. However, trypanosomes lacking this enzyme are more susceptible to bi\u2010 and tri\u2010functional DNA<\/jats:styled-content> alkylating agents with this phenotype readily complemented by ectopic expression of T<\/jats:styled-content>bsnm1<\/jats:italic><\/jats:styled-content>. Genetically modified variants of the null mutant line were subsequently used to establish the anti\u2010parasitic mechanism of action of nitrobenzylphosphoramide mustard and aziridinyl nitrobenzamide prodrugs, compounds previously shown to possess potent trypanocidal properties while exhibiting limited toxicity to mammalian cells. This established that these agents, following activation by a parasite specific type I<\/jats:styled-content> nitroreductase, produce metabolites that promote formation of ICLs<\/jats:styled-content> leading to inhibition of trypanosomal growth.<\/jats:p>","DOI":"10.1111\/mmi.12973","type":"journal-article","created":{"date-parts":[[2015,2,17]],"date-time":"2015-02-17T08:44:57Z","timestamp":1424162697000},"page":"827-838","source":"Crossref","is-referenced-by-count":10,"title":["Unravelling the role of SNM<\/scp>1 in the DNA<\/scp> repair system of T<\/i><\/scp>rypanosoma brucei<\/i>"],"prefix":"10.1111","volume":"96","author":[{"given":"James A.","family":"Sullivan","sequence":"first","affiliation":[{"name":"School of Biological & Chemical Sciences Queen Mary University of London Mile End Road London E1\u20094NS UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie Lun","family":"Tong","sequence":"additional","affiliation":[{"name":"School of Biological & Chemical 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